Ex 3 L5: Topical and Transdermal Drug Delivery

Question 1

Physiology of the skin: Stratum corneum

Answer 1

Stratum corneum
Main barrier to permeation
Brick and mortar model
-Bricks: dead cells
-Mortar: lipid
Dead cells are not permeable
-Gets affected by hydration status
Permeation occurs by partitioning through the lipid material (mortar) between the dead cells (bricks)
Functions as a lipid barrier
State of hydration is directly related to the ease of permeation

Question 2

Physiology of the skin: Living epidermis, dermis, hair follicles and sweat glands

Answer 2

Living epidermis (Viable epidermis)
-Living cells w/o capillaries. Cells get nutrition by diffusion from dermis
-Source of skin color and tanning

Dermis
-Contains capillaries
-Drug needs to reach these capillaries to achieve systemic action
-Contains pain, thermal, and tactile sensors
-Injury must reach dermis to produce scarring
-nerves - feel pain, bleed

hair follicles and sweat glands
-Secondary route of drug absorption that bypasses the stratum corneum

Question 3

Functions of the skin

Answer 3

Containment
-Confine underlying tissues and restrain their movement

Microbial barrier
-pH of skin is 5, which inhibits the growth of bacteria
-Sebum contains bacteriostatic and fungistatic fatty acids (propanoic, butanoic, hexanoic, and heptanoic acids)

Chemical barrier
-Permeability resistance of stratum corneum is several orders of magnitude greater than other barrier membranes of the body

Radiation barrier
-Exposure to UV stimulates synthesis of melanin, which absorbs UV rays

Electrical barrier
-Offers high impedance of the flow of an electrical current
-Need to treat the skin with salt solutions and overcome the impedance to measure body potentials (electroencephalograms or electrocardiograms). Use granular salt suspensions, creams, pastes containing electrolytes

Thermal barrier and body temperature regulation
-Maintains 98.6 degrees F (37C) by dilating/contracting blood vessels or sweating

Question 4

Topical/Transdermal drug delivery

Answer 4

Topical
-Local effects on barrier function
-surface effects
-stratum corneum effects
-Drug action on the skin’s glands
-Effects in deep tissues

Transdermal
-Systemic drug delivery

Question 5

Topical drug delivery

Answer 5

Local effects on barrier function
Surface effects
-Zinc oxide paste for diaper rash
-Sun blocks and sun screens
-Lip balms for chapped lips
-Calamine lotion for poison ivy and poison oak
-Antibiotics
-Deodorants
-Medicated soaps

Stratum corneum effects
-Emoliency: softening horny tissue
-Keratolysis: Chemical digestion and removal of horny tissue

Question 6

Topical Drug Delivery

Answer 6

Drug action on the skin’s glands
-Antiperspirants
-Aluminum chloride (irritate & close the orifice of eccrine glands to impede sweat flow)
-Acne
-Soap, alcoholic solutions, antibiotics,
-Retinoids (reset the processes of epidermal proliferation and differentiation -> prevents the formation of lesions)
-Hair removers (depilatories)

Effects in deep tissues
-Topical corticosteroids
-Non-steroidal anti-inflammatory drugs: diclofenac
Local anesthetics: benzocaine
Lighten excessively pigmented skin: hydroquinone
Skin cancer: 5-fluorouracil

Question 7

Topical drug delivery platforms

Answer 7

Ointments
more hydrophobic
-Hydrocarbon bases
-pertrolatum
-Polyethylene dissolved in mineral oil (Plastibase)
-Silicone bases - contains polydimethylsiloxane oil
-Absorption bases
-Ointment containing W/O emulsifiers (i.e., W/O emulsion containing aqueous solution of a drug)
-Water soluble bases
-Polyethylene glycol ointment
more hydrophilic

Question 8

Topical drug delivery platforms cont.

Answer 8

Pastes
-Ointments into which a high concentration of insoluble particulate solids (starch, calcium carbonate, talc) are added

Creams
-O/W or W/O emulsion

Gels
-Liquid phase trapped in matrix of a natural or synthetic polymer (tragacanth, pectin, carrageenan, methylcellulose, carboxymethylcellulose, carbapol)
-Eg topical scalp gels (not too greasy)

Rigid foams
-Air or other gas emulsified in a liquid phase (like whipped cream)
-Liquid phase may contain a drug
-Aerosol shaving creams, medicated quick-breaking antiseptic foams

Question 9

Transdermal drug delivery

Answer 9

-Some drugs can penetrate the skin and enter systemic circulation
-Of particular interest for drugs that have a short systemic half-life, undergo extensive first-pass metabolism, thus, requiring frequent dosing
have to enter dermis

Question 10

Transdermal drug delivery cont

Answer 10

Generally impenetrable
-Principle resistance is stratum corneum
Permeability correlates with drug’s MW and Ko/w
-LogP ~= -2.7 +0.71logKo/w -0.0061M
-P: permeability coefficient
M: Molecular weight (<1000 Da)
Ko/w: Oil/water partition coefficient
Useful for drugs with:
-High skin permeability
-Low dose requirement

Question 11

Drugs in transdermal patches

Answer 11

Nicotine
Clonidine
Nitroglycerin
-Membrane modulated
-Adhesive dispersion
-Matrix dispersion
Estradiol
Scopolamine
-Membrane modulated
Fentanyl

Question 12

Transdermal nitroglycerin

Answer 12

Nitroglycerin (227.09 Da)
Half-life: 3 min
Slightly soluble in water, soluble in common organic solvents
Indication: Prevention of angina pectoris (Chest pain) due to coronary artery disease; not for immediate relief of acute attacks

Question 13

Transdermal Rivastigmine

Answer 13

Exelon Patch (Novartis)
Approved by FDA: 2007
Indicated for memory problems (dementia0 associated with Alzheimer’s or Parkinson’s disease
4.6 mg/24h, 13.3mg/24h
-A total daily dose of <6mg of oral rivastigmine -> 4.6mg/24h
-A total daily dose of 6-12 mg of oral rivastigmine -> 9.5 mg/24h

Question 14

Transdermal rivastigmine

Answer 14

Rivastigmine
MW: 250.34 Da
Sparingly soluble in water, very soluble in ethanol, acetonitrile, n-octanol, ethyl acetate
LogP: 2.3; water solubility: 2.04 mg/mL

Question 15

Transdermal contraceptive

Answer 15

Ortho Evra (Janssen) - discontinued in 2014
Xualne (Mylan)
150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol
Matrix-type transdermal system
-Backing layer: Polymer layer for structural support
-Middle layer: Adhesive + Matrix + active ingredients
-Third layer: release liner
Once a week for three weeks
Upper outer arm, abdomen, buttock or back

Question 16

Drug diffusion through skin

Answer 16

Protein-rich cells (bricks) separated by thin layer intercellular lipids (mortar)
1. Across the cellular-intercellular regions
2. Across the lipid intercellular spaces
3. Across thin lipid layers sandwiched between the flattened protein cells

Question 17

Factors affecting permeability

Answer 17

Hydration
-The more hydrated, the greater drug permeability
-Water associated with polar head groups of lipid bilayer loosens the lipid packing and make the bilayer more fluid

Question 18

Penetration enhancement

Answer 18

Iontophoresis
-Uses low voltage electrical current to drive charged drugs through the skin

Electroporation
-Uses high voltage (short) to create transient pores in the skin
-Early stage, but very good

Ultrasound
-Uses low frequency ultrasonic energy to disrupt the stratum corneum

prodrugs
-Make lipophilic

(chemical) Penetration enhancers
-Alcohol, dimethyl sulfoxide (DMSO), surfactants, acetone, ethyl acetate

Question 19

Enhancers

Answer 19

Ionic surfactants
-Disorder the lipid layer of stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance

Ascorbate, dithiothreitol
-Reducing agents. Disrupt disulfide bonds of proteins in keratinized cells

Azone
-Nonpolar, oily liquid. Fluidize intracellular lipid lamella region of stratum corneum

Dimethyl sulfoxide (DMSO)
-Dipolar solvent. Enter aqueous region of stratum corneum, interact with the lipid polar heads to expand hydrophilic region between polar heads

Question 20

Microneedles

Answer 20

Dissolving microneedles: type of polymeric MN that can degrade or dissolve postinsertion into the skin, leading to the delivery of the encapsulated drug at the site of application

Hydrogel forming microneedles.
have cross-linked hydrogel structure that can collect interstitial fluid upon skin application -> in-situ hydrogel

Separable microneedles
-Rapidly dissolvable backing layers; with weaker connections between the backing layers and the MN tips; or based on a hydrogel backing layer

Hollow microneedles
-Each needle incorporates a hollow cavity within and a bore on the needle tips, to which small volumes of drug solutions can be injected

Question 21

Patches

Answer 21

Common application sites
-Chest (upper)
-Back (upper and lower)
-Upper arm (on the part facing out)
-Flanks (sides of the body, abdomen level): Except for exelon

Frequency
-Daily (e.g. nicotine, rivastigmine)
-Twice daily (diclofenac)
-Twice weekly
-Weekly (e.g. Buprenorphine, clonidine, estradiol)
-Every 72 hrs (e.g. Fentanyl)

Question 22

Common errors in transdermal patch admin

Answer 22

Preparation
-Removal of the patch from the packaging
-Removal of the protective foil
-Alternation of the patch

Removal
Application
Monitoring
-Influence of heat
-Patch displacement
Storage and disposal

Question 23

Some patients do not realize…

Answer 23

Patch must be applied directly to the skin (they should not tape a patch on top of the other)
They must remove the protective liner
They need to use one patch at a time (6 fentanyl patches)
Where to place (recommended locations; rotate the area of application to avoid skin irriation)
When to change
Transparent patches
TTS: Therapeutic System vs Tues, Thurs, & Saturday
Pediatric patch issue: Some patches should not be cut

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